Rare protein-altering variants in ANGPTL7 lower intraocular pressure and protect against glaucoma

Abstract

Protein-altering variants that are protective against human disease provide in vivo validation of therapeutic targets. Here we use genotyping data from UK Biobank (n = 337,151 unrelated White British individuals) and FinnGen (n = 176,899) to conduct a search for protein-altering variants conferring lower intraocular pressure (IOP) and protection against glaucoma. Through rare protein-altering variant association analysis, we find a missense variant in ANGPTL7 in UK Biobank (rs28991009, p.Gln175His, MAF = 0.8%, genotyped in 82,253 individuals with measured IOP and an independent set of 4,238 glaucoma patients and 250,660 controls) that significantly lowers IOP (β =-0.53 and-0.67 mmHg for heterozygotes,-3.40 and-2.37 mmHg for homozygotes, P = 5.96 x 10 −9 and 1.07 x 10 −13 for corneal compensated and Goldman-correlated IOP, respectively) and is associated with 34% reduced risk of glaucoma (P = 0.0062). In FinnGen, we identify an ANGPTL7 missense variant at a greater than 50-fold increased frequency in Finland compared with other populations (rs147660927, p.Arg220Cys, MAF Finland = 4.3%), which was genotyped in 6,537 glaucoma patients and 170,362 controls and is associated with a 29% lower glaucoma risk (P = 1.9 x 10 −12 for all glaucoma types and also protection against its subtypes including exfoliation, primary openangle, and primary angle-closure). We further find three rarer variants in UK Biobank, including a protein-truncating variant, which confer a strong composite lowering of IOP (P = 0.0012 and 0.24 for Goldman-correlated and corneal compensated IOP, respectively), suggesting the protective mechanism likely resides in the loss of interaction or function. Our results support inhibition or down-regulation of ANGPTL7 as a therapeutic strategy for glaucoma.

Genetic and Functional Characterization of ANGPTL7 as a Therapeutic Target for Glaucoma

“…We performed genetic association analyses of IOP and glaucoma across eight cohorts to identify rare and coding variants that modulate the risk for glaucoma through IOP. This led to the identification of ANGPTL7 as a candidate, consistent with findings reported recently by another group (19). In this report, we 1) strengthen the genetic link to glaucoma protection by (i) showing a consistent protective effect of the Gln175His variant in ANGPTL7 across eight cohorts, (ii) identifying a burden of ultra-rare missense variants in ANGPTL7 that reduce IOP levels, and (iii) identifying an additional rare ANGPTL7 loss-of-function variant in African-ancestry individuals; we also present 2) in vitro characterization of ANGPTL7 variants identified from genetic analyses; and 3) in vivo results showing that mice without Angptl7 have reduced basal IOP, and that even a partial knockdown of Angptl7 with siRNA can lead to lowering of IOP in mice.…”

“…In this study, we present genetic and functional evidence for a role for ANGPTL7 in the physiological control of IOP and as a potential target for glaucoma therapy. Through genetic association analyses across 8 cohorts in Europeans, we confirmed the association of a rare missense variant, Gln175His (rs28991009), in ANGPTL7 with a decrease in IOP and with decreased risk for glaucoma (15,19). We further identified pLOF variants in ANGPTL7, Arg177* (rs143435072) and African ancestry-enriched Trp188* (rs145750805), that also associated with a decrease in IOP, suggesting that Gln175His carriers are protected from glaucoma through a loss or reduction in ANGPTL7 activity.…”

“…We also identified predicted-deleterious ANGPTL7 variants in burden analyses associated with reduced IOP, indicating that there may be other ultra-rare ANGPTL7 variants that confer protection from glaucoma. Supporting this hypothesis, a recent report described the association of one of these ANGPTL7 variants enriched in Finnish individuals (Arg220Cys) with reduced IOP and decreased risk for glaucoma (19).…”

Systematic single-variant and gene-based association testing of thousands of phenotypes in 426,370 UK Biobank exomes

“…These datasets enable the discovery of new disease genes with therapeutic potential at a large scale across phenotypes. For instance, a recent joint association analysis of the UK Biobank and the FinnGen study cohorts revealed rare variants in ANGPTL7 that protect against glaucoma (6). The UK Biobank is a collection of over 500,000 participants with standardized, detailed phenotypic data on which GWAS have been run extensively.…”

The GGLEAM Study: Understanding Glaucoma in the Ohio Amish

“…Previous studies have shown the utility of working with founder populations and population isolates to elucidate genetic variation for glaucoma [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ] and other age-related ocular traits [ 26 , 27 , 28 , 29 ]. The Amish comprise an isolated, founder population that is culturally and genetically segregated from the general population of European descent [ 30 ].…”